CN107530293A - Include the composition that Buddhist nun is replaced according to Shandong - Google Patents
Include the composition that Buddhist nun is replaced according to Shandong Download PDFInfo
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- CN107530293A CN107530293A CN201680020815.3A CN201680020815A CN107530293A CN 107530293 A CN107530293 A CN 107530293A CN 201680020815 A CN201680020815 A CN 201680020815A CN 107530293 A CN107530293 A CN 107530293A
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- pharmaceutical composition
- shandong
- buddhist nun
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- sodium
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- A61K9/4858—Organic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2/00—Processes or devices for granulating materials, e.g. fertilisers in general; Rendering particulate materials free flowing in general, e.g. making them hydrophobic
- B01J2/10—Processes or devices for granulating materials, e.g. fertilisers in general; Rendering particulate materials free flowing in general, e.g. making them hydrophobic in stationary drums or troughs, provided with kneading or mixing appliances
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2/00—Processes or devices for granulating materials, e.g. fertilisers in general; Rendering particulate materials free flowing in general, e.g. making them hydrophobic
- B01J2/22—Processes or devices for granulating materials, e.g. fertilisers in general; Rendering particulate materials free flowing in general, e.g. making them hydrophobic by pressing in moulds or between rollers
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4833—Encapsulating processes; Filling of capsules
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Abstract
There is discussed herein include pharmaceutical composition that Buddhist nun is replaced according to Shandong and preparation method thereof.The composition can be used for treating various disease conditions, including but not limited to B cell proliferation disease, such as NHL (diffusivity large B cell lymphoid tumor, follicular lymphoma, lymphoma mantle cell or Burkitt lymphoma), macroglobulinemia Waldenstron, plasma cell myeloma, chronic lymphocytic leukemia, lymthoma or leukaemia.These compositions are designed to be administered orally.The composition is contained in capsule such as normal capsules or sprinkling capsule, or in liquid preparation such as form of suspension.In one embodiment, described pharmaceutical composition is included according to Shandong for Buddhist nun, its salt, prodrug or metabolin, microcrystalline cellulose, Ac-Di-Sol, NaLS and magnesium stearate.In another embodiment, described pharmaceutical composition is included according to Shandong for Buddhist nun, its salt, prodrug or metabolin, microcrystalline cellulose, sodium carboxymethylcellulose, hydroxypropyl methyl cellulose, citric acid monohydrate compound, disodium hydrogen phosphate, Sucralose, Sodium Methyl Hydroxybenzoate, nipagin A sodium, concentrated hydrochloric acid, sodium hydroxide and water.
Description
Technical field
The present invention relates to include the composition and its application method that Buddhist nun is replaced according to Shandong.
Background technology
Targeted therapy is related to the specific difference between identification of cancer cell and normal cell.These differences, which are used to create, to be targetted
Treatment is to attack cancer cell without damaging normal cell, so as to cause less side effect.Difference is present in various targeted therapies
Between but all disturb growth of cancer cells, division, reparation and/or the ability with other cell communications.
Cancer therapy drug according to Shandong for Buddhist nun for targeting B cell malignant tumour.Being blocked according to Shandong for Buddhist nun stimulates malignant B cell uncontrolled
The growth of system ground and the signal of division.It ratifies to be used to treat lymphoma mantle cell in November, 2013 by US FDA, and in 2014
It is approved for for 2 months in year treating chronic lymphocytic leukemia.It is via half Guang being covalently bound in BTK avtive spots
Histidine residue Cys-481 enzyme, the selective covalency inhibitor (IC of the oral administration of bruton's EGFR-TK (BTK)50
=0.46nM).BTK is the signaling molecule of B cell antigen receptor (BCR) and cytokine receptor path.BCR paths are in a variety of B
In cell malignancies, including it is involved in MCL and B cell CLL.Sold according to Shandong for Buddhist nun in the U.S. in the form of oral capsule
(ImbruvicaTM)。
This area is needed comprising the alternative preparation that Buddhist nun is replaced according to Shandong.
The content of the invention
In one aspect, there is provided pharmaceutical composition, described pharmaceutical composition includes replaces Buddhist nun, its salt, prodrug or metabolism according to Shandong
Thing, microcrystalline cellulose, Ac-Di-Sol, NaLS and magnesium stearate.In one embodiment, it is described
Composition replaces Buddhist nun comprising about 40 to about 45 weight % according to Shandong.
In one aspect, there is provided pharmaceutical composition, described pharmaceutical composition include (i) about 40 to about 45 weight % according to Shandong
For Buddhist nun;(ii) about 44 to about 47 weight % microcrystalline cellulose;(iii) about 6 to about 8 weight % cross-linked carboxymethyl cellulose
Sodium;(iv) about 1 to about 5 weight % NaLS;About 0.2 to about 0.3 weight % magnesium stearate (v).
In another aspect, there is provided pharmaceutical composition, described pharmaceutical composition replace Buddhist nun comprising (i) about 140mg according to Shandong;
(ii) about 151mg microcrystalline cellulose;(iii) about 23mg Ac-Di-Sol;(iv) about 14mg lauryl sulphur
Sour sodium;About 1.6mg magnesium stearate (v).
In another aspect, there is provided pharmaceutical composition, described pharmaceutical composition replace Buddhist nun comprising (i) about 50mg according to Shandong;
(ii) about 54mg microcrystalline cellulose;(iii) about 8mg Ac-Di-Sol;(iv) about 5mg lauryl sulfate
Sodium;About 0.6mg magnesium stearate (v).
In another aspect, there is provided capsule and pouch, it includes at least one of pharmaceutical composition as described herein.
In some embodiments, capsule is standard or sprinkling capsule.
In another aspect, there is provided pharmaceutical composition, described pharmaceutical composition includes replaces Buddhist nun, its salt, prodrug or generation according to Shandong
Thank thing, microcrystalline cellulose, sodium carboxymethylcellulose, hydroxypropyl methyl cellulose, citric acid monohydrate compound, disodium hydrogen phosphate, three
Chlorine sucrose, Sodium Methyl Hydroxybenzoate, nipagin A sodium, concentrated hydrochloric acid, sodium hydroxide and water.
In another aspect, there is provided pharmaceutical composition, described pharmaceutical composition replace Buddhist nun comprising (i) about 70mg/mL according to Shandong;
(ii) combination of about 13mg microcrystalline cellulose and sodium carboxymethylcellulose;(iii) about 2.5mg/mL hydroxypropyl methyl fiber
Element;(iv) about 1.5mg/mL citric acid monohydrate compound;(v) about 1.4mg/mL disodium hydrogen phosphate;(vi) the three of about 1mg/mL
Chlorine sucrose;(vii) about 1mg/mL Sodium Methyl Hydroxybenzoate;(viii) about 0.6mg/mL ethyl-para-hydroxybenzoate
Sodium.
In other side, there is provided pharmaceutical composition, described pharmaceutical composition replace Buddhist nun comprising (i) about 40mg/mL according to Shandong;
(ii) combination of about 14mg microcrystalline cellulose and sodium carboxymethylcellulose;(iii) about 1mg/mL hydroxypropyl methyl cellulose;
(iv) about 1.5mg/mL citric acid monohydrate compound;(v) about 1.4mg/mL disodium hydrogen phosphate;(vi) about 0.5mg/mL trichlorine
Sucrose;(vii) about 1.4mg/mL Sodium Methyl Hydroxybenzoate;(viii) about 0.6mg/mL ethyl-para-hydroxybenzoate
Sodium.
In another aspect, there is provided the method for treating B cell proliferation disease, methods described are included at least one
The step of pharmaceutical composition as described herein is administered to subject in need thereof.In certain embodiments, the B is thin
Born of the same parents' proliferative diseases are NHL, macroglobulinemia Waldenstron, plasma cell myeloma or chronic lymphatic
Cell leukemia.
In another aspect, there is provided the method for treating lymthoma, methods described includes will be at least one described herein
Composition be administered to subject in need thereof.
In another aspect, there is provided the method for treating leukaemia, methods described includes will be at least one described herein
Composition be administered to subject in need thereof.
In another aspect, there is provided for treat received to lymphoma mantle cell it is at least one formerly treat by
The method of lymphoma mantle cell in curer, methods described include once a day applying at least one composition as described herein
With to subject.
In another aspect, this paper treatment method is directed to use with spraying capsule, and the sprinkling capsule is opened to contribute to
The content of capsule is sprayed onto in food or beverage.In one embodiment, the beverage is water.In another embodiment party
In case, the food is pap.Capsule 's content can also put into suitable carrier such as water, milk or other common drinks
After in material, it is administered via feeding tube.It note that suspension formulation can also be administered via feeding tube.
In another aspect, there is provided the method for preparing composition as described herein, methods described include:(a) will be micro-
Crystalline cellulose, Part I NaLS and the blending of Part I Ac-Di-Sol;(b) by step (a)
Product and Part I are blended according to Shandong for Buddhist nun;(c) product of step (b) and Part II are blended according to Shandong for Buddhist nun;(d) will
The product of step (c) and the magnesium stearate of Part I are blended;(e) product of calandering steps (d);(f) made in grinding steps (e)
The ribbon obtained;(g) by obtained particle in step (e) and the NaLS and cross-linked carboxymethyl cellulose of Part II
Sodium is blended;And (h) magnesium stearate of the product of step (g) and Part II is blended.In one embodiment, the side
Method also includes the product that (i) adds step (h) to capsule.
In another aspect, there is provided the method for preparing composition as described herein, methods described include:(a) by water, crystallite
Cellulose, Ac-Di-Sol mixing;(b) water is mixed with hydroxypropyl methyl cellulose;(c) by the production of step (b)
Thing mixes with according to Shandong for Buddhist nun;(d) step (a) and (c) product are mixed;(e) product of step (d) is mixed with Sucralose
Close;(f) product of step (e) is mixed with Sodium Methyl Hydroxybenzoate and nipagin A sodium;(g) by step
(f) product mixes with monohydrate potassium;And (h) mixes the product of step (g) with ADSP.At one
In embodiment, it is about 6 that the pH of the product of step (h) is also adjusted to pH by methods described including (i).In another embodiment
In, methods described also includes adding water to step (h) or (i) product.In another aspect, methods described also includes combining
Thing is added in bottle.
Other aspects and advantages of the present invention be also described in its preferred embodiment it is described further below in.
Brief description of the drawings
The application is further understood when read in conjunction with the accompanying drawings.For the purpose of explanation theme, institute is shown in the drawings
State the exemplary of theme;But presently disclosed theme is not limited to concrete composition disclosed in this invention, method, dress
Put and system.In addition, accompanying drawing is not necessarily drawn to scale.
Fig. 1 is provided for preparing comprising the process chart according to Shandong for the capsule of Buddhist nun.
Fig. 2 is provided for preparing comprising the process chart according to Shandong for the liquid preparation of Buddhist nun.
Fig. 3 is provided for preparing on a large scale comprising the process chart according to Shandong for the liquid preparation of Buddhist nun.
Embodiment
, can be more easily with reference to the following detailed description of the appended drawings and examples to forming a disclosure part
Understand the present invention.It should be appreciated that the invention is not restricted to specific product, method, condition or ginseng described herein and/or show
Number, and terms used herein is only used for describing specific embodiment by way of example, it is no intended to and limitation is by claims
The present invention of protection.Similarly, unless otherwise indicated, otherwise on possible mechanism or binding mode or improve reason it is any
Description is only intended to for exemplary purposes, and the disclosure herein not mechanism by any such suggestion or binding mode or improvement
The constraint correctly or incorrectly of reason.Herein, it should be appreciated that illustrate to be related to preparation and use composition as described herein
Feature structure and method.
In the disclosure, unless context explicitly points out on the contrary, otherwise odd number "one", " one kind " and "the" include it is multiple
Number implication, the reference to concrete numerical value comprise at least the concrete numerical value.Thus, for example when referring to " a kind of material ", refer to
A kind of few such material, and equivalent of the material known to those skilled in the art, etc..
When using describing language " about " or value " substantially " being expressed as into approximation, it will be appreciated that the occurrence constitutes
Another embodiment.In general, the use instruction of term " about " or " substantially " can be according to theme disclosed in this invention
Required characteristic variations to be obtained and by the approximation particularly explained below based on its function using it.This
The technical staff in field routinely can explain to it.In some cases, for occurrence effective digital number
Mesh can be a kind of non-limiting method for the degree for determining word " about " or " substantially ".In other cases, for a series of
The gradient of value can be used for the desired extent that term " about " or " substantially " are determined for each value.In case of presence, own
Scope includes endpoint value and is combined.That is, when mentioning the value with range format statement, including the scope
Interior each value.
When providing a list, unless otherwise noted, it should be understood that in the list it is each individually element and should
Every kind of combination of list will be considered as single embodiment.For example, with " the embodiment list that A, B or C " are provided will by regarding
It is to include embodiment " A ", " B ", " C ", " A or B ", " A or C ", " B or C " or " A, B or C ".
It should be appreciated that for clarity, some features of the invention are illustrated in the context of independent embodiment,
But can also combining form provide in single embodiment.That is, unless obvious incompatible or be left out, otherwise
Each individually embodiment is considered as can be with any other combination of embodiment, and this combination is considered as another embodiment party
Case.On the contrary, for simplicity, various features of the invention are illustrated in the context of single embodiment, also can be single
Solely or in the form of any sub-portfolio provide.It shall also be noted that claims can be established as excluding any optional element.Together
Sample, this statement is intended to when the statement " individually " with reference to claim element, " uniquely " etc. use such proprietary term
When, or use it is " negative " limit when serve as antecedent basis.Finally, when embodiment can be described as a part or more for series of steps
During a part for universal structure, each step also can be considered an independent embodiment in itself.
As used herein, term " subject " refers to that needs replace the sanatory animal of Buddhist nun according to Shandong.In an embodiment party
In case, subject behaves.In another embodiment, subject is to be grown up, including teenager, adult, the elderly
Or children, including teenager.
As used herein, term " purified " preferably refers to replace Buddhist nun according to Shandong comprising less than about 1% impurity.In a reality
Apply in scheme, less than about 0.5% impurity is included for Buddhist nun according to Shandong.In another embodiment, included less than about for Buddhist nun according to Shandong
0.1% impurity.In another embodiment, it is about 100% pure for Buddhist nun according to Shandong.
As used herein, it is known in term particle and in the external formulation art of particle.Before particle formation, addition
Form in the particle of formulation components.Similarly, before the compression, form outside the particle of formulation components is added to the particle of preparation
In.Briefly, composition is resolved into particle by extra-granular point, and particle inside points replace intragranular disintegration to discharge according to Shandong
Buddhist nun, its salt, prodrug or metabolin.
Abbreviation used herein includes CCS (Ac-Di-Sol), MCC (microcrystalline cellulose), SLS (lauryls
Sodium sulphate), HPMC (hydroxypropyl methyl celluloses;Hydroxypropyl methylcellulose), DSC (differential scanning calorimetry (DSC)), BHT (butylation hydroxyls
Base toluene), BHA (butylated hydroxyanisol), Sodium Methyl Hydroxybenzoate, nipagin A sodium, CLL it is (chronic
Lymphocytic leukemia) and SLL (small lymphocyte lymthoma).
A. Buddhist nun's form is replaced according to Shandong
Composition as described herein includes is used as activating agent according to Shandong for Buddhist nun (Imbruvica).Buddhist nun's such as United States Patent (USP) is replaced according to Shandong
7,514,444th, described in 8,003,309,8,697,711,8,735,403,8,957,079 and 8,754,091 and can be as wherein
Shown preparation, the patent document are herein incorporated by reference.As it is known in the art, for Buddhist nun it is 1- [(3R) -3- according to Shandong
[4- amino -3- (4- phenoxy phenyls) -1H- pyrazolos [3,4d] pyrimidine -1- bases] -1- piperidyls] -2- propylene -1- ketone and have
Following structure.According to Shandong for Buddhist nun with about 149 DEG C to about 158 DEG C of melting range, about 4 distribution coefficient in the case where pH is 7, about 3.7
Dissociation constant, and DSC fusing points originated at about 156 DEG C.
Used herein to may include other forms, including its metabolin according to Shandong for Buddhist nun, precondition is to replace Buddhist nun's form according to Shandong
It is stable and atoxic.Can also have basis to replace some of Buddhist nun's molecule according to Shandong or replaced with the basis according to Shandong for Buddhist nun's form according to Shandong
Buddhist nun's molecule identical activity.In one embodiment, there is following structure for the active metabolite of Buddhist nun according to Shandong.
Buddhist nun's form is replaced to may include the tautomeric form for replacing Buddhist nun, prodrug and salt according to Shandong according to Shandong for this paper.In a reality
Apply in scheme, can be derived from pharmaceutically or physiologically acceptable acid, alkali, alkali and alkaline earth metal ions for Buddhist nun according to Shandong.Physiologically
Acceptable acid is included from those of inorganic acid and organic acid.Inorganic acid be well known in the art and including but it is unlimited
In hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid and phosphoric acid.Organic acid is also known in the art, and including but not
It is limited to lactic acid, formic acid, acetic acid, fumaric acid, citric acid, propionic acid, oxalic acid, butanedioic acid, glycolic, glucuronic acid, maleic acid, chaff
Acid, glutamic acid, benzoic acid, ortho-aminobenzoic acid, salicylic acid, tartaric acid, malonic acid, malic acid, phenylacetic acid, mandelic acid, flutter acid,
Methanesulfonic acid, ethyl sulfonic acid, pantothenic acid, benzene sulfonic acid, toluenesulfonic acid, stearic acid, sulfanilic acid, alginic acid and galacturonic acid.Inorganic base exists
It is in this area and known, and the including but not limited to sulfate or phosphate of aluminium, calcium, lithium, magnesium, potassium, sodium and zinc.It is similar
Ground, organic base are also known, and including but not limited to N, N- dibenzyl-ethylenediamin, chloroprocanine, courage in the art
Alkali, diethanol amine, ethylenediamine, meglumine and procaine.Alkali and alkaline earth metal ions salt may include but be not limited to be in ester and ammonia
Sodium, potassium, calcium and the magnesium salts of carbamate form.
It will also be appreciated that according to Shandong for the prodrug and including but not limited to ester, carbamate, sulfate, ether, oxime, carbon of Buddhist nun
Hydrochlorate etc..When being administered in the form of such, prodrug forms are converted into active part in vivo.Referring to Testa, " Prodrugs
Revisited:The " Ad Hoc " Approach as a Complement to Ligand Design ", Medicinal
Research Reviews, 16 (3):233-241, editor, John Wiley&Sons (1996), it is herein incorporated by reference
Herein.
It can also be utilized as described herein for " metabolin " of Buddhist nun according to Shandong.As it is known in the art, metabolin is to work as chemical combination
The compound that Buddhist nun is replaced according to Shandong that thing is formed when being metabolized, such as " The Pharmacological Basis of Therapeutics ",
9th edition, described in McGraw-Hill (1996), it is herein incorporated by reference.
B. solid pharmaceutical preparation
It can be formulated for delivering medicine to subject with solid dosage form for Buddhist nun according to Shandong.Solid pharmaceutical preparation is essentially dry
, i.e. without liquid.In one embodiment, solid pharmaceutical preparation is about 90% or more drying.
In one embodiment, pharmaceutical composition as described herein include according to Shandong for Buddhist nun, its salt, prodrug or metabolin,
Microcrystalline cellulose, Ac-Di-Sol, NaLS and magnesium stearate.As described above, included in said composition
According to Shandong for Buddhist nun can based on molecule, salt, prodrug or its metabolin.
The composition replaces Buddhist nun, its salt, prodrug or metabolin comprising about 40 to about 45 weight % according to Shandong.In an implementation
In scheme, the composition replaces Buddhist nun, its salt, prodrug or metabolin comprising about 41 to about 44 weight % according to Shandong.In another reality
Apply in scheme, the composition replaces Buddhist nun, its salt, prodrug or metabolin comprising about 42 to about 43 weight % according to Shandong.At another
In embodiment, the composition replaces Buddhist nun, its salt, prodrug or metabolin comprising about 42 or about 43 weight % according to Shandong.Another
In individual embodiment, the composition replaces Buddhist nun, its salt, prodrug or metabolin comprising about 50 to about 140mg according to Shandong.At another
In embodiment, the composition replaces Buddhist nun, its salt, prodrug or metabolin comprising about 50mg according to Shandong.
One or more suspending agents can be included in fluid composition as described herein.In one embodiment, this paper institutes
Microcrystalline cellulose can be also included in the composition stated.In another embodiment, the composition includes about 44 to about 47 weights
Measure % microcrystalline cellulose.In another embodiment, the composition includes about 45 to about 46 weight % microcrystalline cellulose
Element.
The composition also includes Ac-Di-Sol.The Ac-Di-Sol can be in particle
Or the outer form of particle.In one embodiment, the composition includes about 6 to about 8 weight % cross-linked carboxymethyl cellulose
Sodium.In another embodiment, the composition includes about 7 weight % Ac-Di-Sol.In another reality
Apply in scheme, the composition includes about 3 to about 5 weight % intra-particle crosslink sodium carboxymethylcellulose.In another implementation
In scheme, the composition includes about 4 weight % intra-particle crosslink sodium carboxymethylcellulose.In another embodiment,
The composition includes about 2 to about 4 weight % extragranular connection sodium carboxymethylcellulose.In another embodiment, institute
State the Ac-Di-Sol that composition includes about 3 weight %.In another embodiment, the composition includes about
13mg intra-particle crosslink sodium carboxymethylcellulose and about 9.9mg extragranular connection sodium carboxymethylcellulose.In another reality
Apply in scheme, the composition includes about 4.6mg intra-particle crosslink sodium carboxymethylcellulose and about 3.5mg extragranular joins
Sodium carboxymethylcellulose.
NaLS can be also included in composition as described herein.NaLS can be in particle or particle
Outer form.In one embodiment, the composition includes about 1 to about 5 weight % NaLS.In another reality
Apply in scheme, the composition includes about 2 to about 4.5 weight % NaLS.In another embodiment, it is described
Composition includes about 3 to about 4 weight % NaLS.In another embodiment, the composition includes about 2.5
NaLS in about 3 weight % particle.In another embodiment, the composition includes about 3 weight %'s
NaLS in particle.In another embodiment, the composition includes the moon outside about 1 to about 2 weight % particle
Osmanthus base sodium sulphate.In another embodiment, the composition includes the about 1.4 weight % outer NaLS of particle.
In another embodiment, the composition is included in about 9.4mg particle outside NaLS and about 4.6mg particle
NaLS.In another embodiment, the composition includes NaLS peace treaty in about 3.3mg particle
The outer NaLS of 1.6mg particle.
Composition as described herein can also include magnesium stearate.Magnesium stearate can be in particle or the outer form of particle.
In one embodiment, the composition includes about 0.4 to about 0.6 weight % magnesium stearate.In another embodiment,
The composition includes about 0.4 to about 0.5 weight % magnesium stearate.In another embodiment, the composition includes
About 0.45 to about 0.5 weight % magnesium stearate.In another embodiment, the composition includes about 0.2 to about 0.3 weight
Measure magnesium stearate in % particle.In another embodiment, the composition includes about 0.2 to about 0.3 weight %
The outer magnesium stearate of grain.In another embodiment, the composition includes magnesium stearate peace treaty in about 0.8mg particle
0.8mg extragranular magnesium stearate.In another embodiment, the composition includes stearic acid in about 0.3mg particle
Magnesium and about 0.3mg extragranular magnesium stearate.
In one embodiment, pharmaceutical composition is described herein and comprising material in particle, in the particle
Material is included according to Shandong for Buddhist nun, its salt, prodrug or metabolin, microcrystalline cellulose, Ac-Di-Sol, NaLS
And magnesium stearate.
In another embodiment, pharmaceutical composition includes the outer material of particle, and the outer material of the particle includes crosslinking carboxylic
Sodium carboxymethylcellulose pyce, NaLS and magnesium stearate.
In another embodiment, there is provided pharmaceutical composition and comprising:(i) about 40 to about 45 weight % replace according to Shandong
Buddhist nun;(ii) about 44 to about 47 weight % microcrystalline cellulose;(iii) about 6 to about 8 weight % Ac-Di-Sol;
(iv) about 1 to about 5 weight % NaLS;About 0.2 to about 0.3 weight % magnesium stearate (v).
In another embodiment, there is provided pharmaceutical composition and comprising:(i) about 140mg according to Shandong replaces Buddhist nun;(ii) about
151mg microcrystalline cellulose;(iii) about 23mg Ac-Di-Sol;(iv) about 14mg NaLS;With
(v) about 1.6mg magnesium stearate.
In another embodiment, there is provided pharmaceutical composition and comprising:(i) about 50mg according to Shandong replaces Buddhist nun;(ii) about
54mg microcrystalline cellulose;(iii) about 8mg Ac-Di-Sol;(iv) about 5mg NaLS;(v)
About 0.6mg magnesium stearate.
In another embodiment, there is provided pharmaceutical composition, described pharmaceutical composition include the component in table 1.
Table 1
Solid composite as described herein is included with optimum size to allow the particle that composition dissolves, such as described
Grain is less than or equal to about 10 μ.The size of the particle of the composition can by make solid composite by it is various sizes of sieve come
Measurement.If the particle of the composition be more than optimum size and if the particle of the composition be not encapsulated in capsule or
It is dissolved in one or more excipient, then the particle of the composition can be subjected to further grinding and screening step etc., to subtract
Small grain size.Optionally under a nitrogen and the conventional micronization technology not being micronized according to Shandong for Buddhist nun can be applied to according to Shandong for Buddhist nun, for example, it is sharp
It is micronized with Trost or jet mill.However, composition as described herein is not limited to thus prepare the method for replacing Buddhist nun according to Shandong.According to
Shandong can have for Buddhist nun is less than about 10 μm, the median particle less than about 7 μm or less than about 5 μm.Specifically, 90% particle is less than
Or equal to about 10 μm, and 50% particle less than or equal to about 10 μm, as determined as Malvern methods, it is ability
Field technique personnel are readily appreciated by.
Various equipment can be used for prepare the manufacturing process of solid composite, and including small size, middle size and greatly
The bag of size, various sizes of sieve, and mixer.Methods described may also include mixing, extrusion, melting, compacting and/or grinding group
Compound, its compacting machine and grinder for being selected usually using those skilled in the art.Grinding steps can be to various sizes of particle
(that is, bulky grain, powder and fine powder) is carried out to obtain granularity evenly.Grinding may include one or more separation, follow again
Ring and screening step are to obtain desired granularity.In one embodiment, the composition can be by based on the total of composition
Weight, according to Shandong other components of Buddhist nun and composition will be replaced dry-mixed to prepare.In another embodiment, combination as described herein
Thing can will replace other component wet mixings of Buddhist nun and composition to prepare by the gross weight based on composition according to Shandong.Dry and can be used
Carried out by the drying instrument of those skilled in the art's selection.See, e.g., Lachman, " The Theory and
Practice of Industrial Pharmacy ", the 3rd edition, (1986), it is herein incorporated by reference.
In one embodiment, solid composite as described herein is prepared by the following method:(a) by microcrystalline cellulose
Element, Part I NaLS and the blending of Part I Ac-Di-Sol;(b) by the product of step (a) with
Part I is blended according to Shandong for Buddhist nun;(c) product of step (b) and Part II are blended according to Shandong for Buddhist nun;(d) by step
(c) product and the magnesium stearate of Part I is blended;(e) product of calandering steps (d);(f) it is obtained in grinding steps (e)
Ribbon;(g) NaLS and Ac-Di-Sol of obtained particle and Part II in step (f) are total to
It is mixed;And (h) magnesium stearate of the product of step (g) and Part II is blended.In another embodiment, solid compositions
Thing preparation as shown in Figure 1.
Then, solid composite can be formed as to being suitably administered unit to be delivered to patient, such as pass through art technology
Determined by personnel.Suitable administration unit includes oral dosage unit.In one embodiment, add and combine to capsule
Thing.In another embodiment, capsule is used for pediatric administration.In another embodiment, capsule is used for by that can not swallow
The adult of solid pharmaceutical preparation applies.In other embodiments, capsule is HPMC (hydroxypropyl methylcellulose) capsule.Another
In individual embodiment, capsule is gelatine capsule.In another embodiment, capsule is hard gelatin capsule.In another implementation
In scheme, capsule is standard or sprinkling capsule.In another embodiment, capsule is Sweden's orange capsule.In another implementation
In scheme, capsule is No. 0 capsule.In another embodiment, can open sprinkling capsule and by content add can by by
In the material such as food or beverage of curer's intake.The food can be semi-solid or solid, including pap.
In another embodiment, comprising according to Shandong for Buddhist nun capsule for film coating.Suitable film coating will be ability
Known to field technique personnel.For example, film coating can be polymer such as HPMC, ethyl cellulose, polyvinyl alcohol or they
Combination.
Solid composite can be also added in pouch.As used herein, term " pouch " be refer to accommodate it is described herein
Composition bag or case.The size of pouch depends on the amount of composition to be added.In one embodiment, the pouch
For single dose pouch.In another embodiment, the pouch includes a large amount of compositions as described herein.In latter case
Under, patient, doctor or care-giver measure the suitable dosage of the composition for administration.In another embodiment, it is described small
Bag is paper/aluminium/polyethylene laminate or polyester/aluminium/polyethylene laminate, and both can optionally be provided with barrier coat, such as second
Alkene-vinyl acetate, polyvinyl acetate, polysiloxanes or melamine etc..In another embodiment, pouch can be opened
And by content add can by subject absorb material such as food or beverage in.The beverage may include but be not limited to
Water, milk or other conventional beverages.
The liquid preparation (preparing in liquid form) of solid composite can deliver medicine to subject via feeding tube.The feeding tube
The technology of this area can be used temporarily or permanently to be attached to patient.As needed, patient can be it is clear-headed, semiconsciousness,
Or sleep soundly, as determined by attending doctor.Polytype feeding tube is well known in the art and can be by curing mainly doctor
Teacher selects.
C. liquid preparation
It can be formulated for delivering medicine to subject with liquid forms for Buddhist nun according to Shandong.Liquid includes but is not limited to suspend
Liquid, syrup and elixir.These administration units easily using method described herein and it is well known by persons skilled in the art those
Prepare.When being configured to suspension, particle sedimentation can occur, so as to need to use the technology of this area to be resuspended in particle
In suspension.
Fluid composition as described herein is included according to Shandong for Buddhist nun, its salt, prodrug or metabolin, microcrystalline cellulose, carboxymethyl
Sodium cellulosate, hydroxypropyl methyl cellulose, citric acid monohydrate compound, disodium hydrogen phosphate, Sucralose, methyl p-hydroxybenzoate
Sodium, nipagin A sodium, concentrated hydrochloric acid, sodium hydroxide and water.
Therefore, the fluid composition replaces Buddhist nun, its salt, prodrug or metabolin comprising about 30 to about 80mg/mL according to Shandong.
In some embodiments, the composition replaces Buddhist nun, its salt, prodrug or metabolin comprising about 30 to about 50mg/mL according to Shandong.Another
In one embodiment, the composition replaces Buddhist nun, its salt, prodrug or metabolin comprising about 40mg/mL according to Shandong.In other implementations
In scheme, the composition replaces Buddhist nun, its salt, prodrug or metabolin comprising about 60 to about 80mg/mL to about 70mg/mL according to Shandong.
In another embodiment, the composition replaces Buddhist nun, its salt, prodrug or metabolin comprising about 70mg/mL according to Shandong.
One or more suspending agents can be included in fluid composition as described herein.In one embodiment, the liquid
Microcrystalline cellulose and sodium carboxymethylcellulose can be also included in body composition.In some embodiments, the composition includes
About 12 to about 15mg/mL suspending agent.In another embodiment, the composition include about 13 to about 15mg/mL it is outstanding
Floating agent.In other embodiments, the composition includes about 12 to about 14mg/mL suspending agent.In another embodiment
In, the composition includes about 13mg/mL suspending agent.In another embodiment, the composition includes about 14mg/mL
Suspending agent.
The composition can also include the one or more in wetting agent.In one embodiment, the composition bag
Containing hydroxypropyl methyl cellulose.In some embodiments, the composition includes about 0.5 to about 3mg/mL wetting agent.
In other embodiments, the composition includes about 2 to about 3mg/mL wetting agent.In another embodiment, described group
Compound includes about 2.5mg/mL wetting agent.In another embodiment, the composition includes about 0.5 to about 1.5mg/mL
Wetting agent.In other embodiments, the composition includes about 1mg/mL wetting agent.
One or more buffers can be included in solid or fluid composition.In one embodiment, buffer is lemon
Lemon acid monohydrate or disodium hydrogen phosphate.In another embodiment, the composition includes about 2.5 to about 3.5mg/mL's
Buffer.In some embodiments, the composition includes about 1 to about 1.5mg/mL the first buffer.In other implementations
In scheme, the composition includes about 0.5 to about 0.7mg/mL buffer.In another embodiment, the composition
Second buffer of the first buffer and about 1.5mg/mL comprising about 1.5mg/mL.In other embodiments, the combination
Thing includes about 1.6mg/mL the first buffer and about 1.4mg/mL the second buffer.In another embodiment, it is described
Composition includes about 1.5mg/mL or 1.6mg/mL citric acid monohydrate compound.In another embodiment, the composition
Include about 1.4mg/mL disodium hydrogen phosphate.
Sweetener can be also included in solid as described herein or fluid composition.In one embodiment, the sweet tea
Taste agent is Sucralose.In another embodiment, the composition includes about 0.1 to about 1.5mg/mL sweetener.
In other embodiments, the composition includes 0.5 to about 1.5mg/mL sweetener.In another embodiment, it is described
Composition includes about 1mg/mL sweetener.In another embodiment, the composition includes about 0.5mg/mL sweet taste
Agent.
One or more preservatives can be also included in the solid or fluid composition.The preservative is in liquid preparation
Advantageously provide optimal microbial activity.In one embodiment, the composition retains methyl hydroxybenzoate/nipalgin second
The optimum activity of ester.In one embodiment, the preservative is Sodium Methyl Hydroxybenzoate.In another embodiment
In, the preservative is nipagin A sodium.In another embodiment, the composition includes about 1.5 to about
2.5mg/mL preservative.In other embodiments, the composition includes about 1.5 to about 2mg/mL preservative.Another
In one embodiment, the composition includes about 0.5 to about 1.8mg/mL the first preservative.In another embodiment
In, the composition includes about 1.0 to about 1.8mg/mL the first preservative.In another embodiment, the composition
Include about 1.25 to about 1.5mg/mL the second preservative.In another embodiment, the composition includes about 1.1mg/
ML the first preservative and about 0.6mg/mL the second preservative.In other embodiments, the composition includes about
1.4mg/mL the first preservative and about 0.7mg/mL the second preservative.In another embodiment, the composition bag
Sodium Methyl Hydroxybenzoate containing about 1mg/mL.In another embodiment, the composition includes about 0.6mg/mL's
Nipagin A sodium.In a further embodiment, the composition includes about 1.4mg/mL P-hydroxybenzoic acid
Methyl esters sodium.In another embodiment, the composition includes about 0.7mg/mL nipagin A sodium.
If the pH of solution needs to adjust, pH adjusting agent can be included in the composition.Those skilled in the art will
Suitable pH adjusting agent can be selected to ensure the safe and stable composition compatible with subject.In one embodiment,
The pH value of composition is adjusted to about 6.In another embodiment, pH adjusting agent is acid or alkali.In another embodiment
In, pH adjusting agent is hydrochloric acid.In another embodiment, pH adjusting agent is concentrated hydrochloric acid.In another embodiment, pH is adjusted
Section agent is sodium hydroxide.
Finally, the combination kind can include enough diluents, such as water, to ensure about 1mL volume.In an implementation
In scheme, the diluent is purified water.Can be as described herein by using dilution for the composition of Buddhist nun according to Shandong comprising small amount
Dilution agent includes a greater amount of to be prepared according to Shandong for the composition of Buddhist nun.
In one embodiment, there is provided pharmaceutical composition and comprising:(i) about 70mg/mL according to Shandong replaces Buddhist nun;(ii) about
13mg microcrystalline cellulose and sodium carboxymethylcellulose;(iii) about 2.5mg/mL hydroxypropyl methyl cellulose;(iv) about
1.5mg/mL citric acid monohydrate compound;(v) about 1.4mg/mL disodium hydrogen phosphate;(vi) about 1mg/mL Sucralose;
(vii) about 1mg/mL Sodium Methyl Hydroxybenzoate;(viii) about 0.6mg/mL nipagin A sodium.
In another embodiment, there is provided pharmaceutical composition and the component for including table 2.
Table 2
Component | Concentration (mg/mL) |
Buddhist nun is replaced according to Shandong, is micronized | 70 |
MCC knows CMC | 13 |
HPMC | 2.5 |
Citric acid monohydrate compound | 1.513 |
Disodium hydrogen phosphate | 1.38 |
Sucralose | 1 |
Sodium Methyl Hydroxybenzoate | 1.145 |
Nipagin A sodium | 0.575 |
In other embodiments, there is provided pharmaceutical composition and comprising:(i) about 40mg/mL according to Shandong replaces Buddhist nun;(ii) about
14mg microcrystalline cellulose and sodium carboxymethylcellulose;(iii) about 1mg/mL hydroxypropyl methyl cellulose;(iv) about 1.6mg/
ML citric acid monohydrate compound;(v) about 1.4mg/mL disodium hydrogen phosphate;(vi) about 0.5mg/mL Sucralose;(vii) about
1.4mg/mL Sodium Methyl Hydroxybenzoate;(viii) about 0.7mg/mL nipagin A sodium.
In other embodiments, there is provided pharmaceutical composition and the component for including table 3.
Table 3
Component | Concentration (mg/mL) |
Buddhist nun is replaced according to Shandong, is micronized | 40 |
MCC and CMC | 14 |
HPMC | 1 |
Citric acid monohydrate compound | 1.602 |
Disodium hydrogen phosphate | 1.38 |
Sucralose | 0.5 |
Sodium Methyl Hydroxybenzoate | 1.3582 |
Nipagin A sodium | 0.6773 |
The fluid composition can be prepared by the following method:(a) by water, microcrystalline cellulose, cross-linked carboxymethyl cellulose
Sodium mixes;(b) water is mixed with hydroxypropyl methyl cellulose;(c) product of step (b) is mixed with according to Shandong for Buddhist nun;(d) will step
Suddenly the product of (a) and (c) mixes;(e) product of step (d) is mixed with Sucralose;(f) by the product of step (e) with it is right
Methyl hydroxybenzoate sodium and nipagin A sodium mixing;(g) product of step (f) is mixed with monohydrate potassium
Close;And (h) mixes the product of step (g) with ADSP.Methods described may also include (i) by step (h)
It is about 6 that the pH of product, which is adjusted to pH,.In one embodiment, step (i) is carried out using hydrochloric acid or sodium hydroxide.Methods described
Also include adding water to step (h) or (i) product.It is also contemplated that techniques known in the art can be used by the production of step (a)
Thing is homogenized.
Liquid preparation may then act as body unit storage or be assigned in independently smaller bottle with by consumer
Storage or purchase.Those skilled in the art will be readily able to bottle of the selection suitable for this paper.In one embodiment, will
The fluid composition is added in bottle.In a further embodiment, the bottle is glass.In another embodiment
In, the bottle is transparent or amber.In a further embodiment, the bottle can seal.In another reality
Apply in scheme, the bottle rubber stopper seal.In a further embodiment, the rubber stopper that the bottle is coated with teflon
Sealing.The plug optionally includes removable, you can the aluminium lid of tearing.In another embodiment, bottle 10mL/
20mm bottles.In a further embodiment, bottle is beverage bottle.
In addition, after suitable sample is shaken so that particle to suspend again before administration, drug products will be with single dose
Form delivers medicine to each subject.In addition, after drug products administration, bottle will be rinsed with suitable quantity of water, and bottle is complete
Portion's content will deliver medicine to subject.For the reason for mentioned above, even if sedimentation occurs, it is also contemplated that not having to dosage delivered
Have an impact.
D. annexing ingredient
Other components can be added in composition as described herein, as identified by the skilled person.Additional group
It can be function that is inert and not disturbing required composition component to divide.Therefore, composition may include other auxiliary agents, sugar
Slurry, elixir, diluent, adhesive, lubricant, surfactant, granulating agent, disintegrant, emollient, metal-chelator, pH are adjusted
Save agent, colored preservative, antioxidant, medicament, surfactant, filler, disintegrant or combinations thereof.
Preservative may include ascorbic acid, BHT and BHA, Sodium Methyl Hydroxybenzoate, nipagin A sodium or
Combinations thereof.
Sweetener is such as natural or artificial sweetener or combinations thereof can be included in composition as described herein.
In one embodiment, natural sweetener is Sucralose, including raw sugar, granulated sugar, brown sugar, Icing Sugar and rape sugar, fructose, honeybee
Honey, fruit drops, high-fructose corn syrup, corn syrup, sugar alcohol such as mannitol, sorbierite, xylitol, antierythrite, hydrogenation
Starch hydrolysate, lactitol or maltitol, osmalt, glucose, inverted sugar, American aloe nectar, glucose, lactose, wheat
Bud sugar, maple sugar, date sugar, molasses, qualities of stevia extract, Tagatose, trehalose or any combination of them.Another embodiment party
Case, artificial sweetener are Sucralose, Aspartame, saccharin, neotame, saccharin or acesulfame potassium.In another embodiment party
In case, sugar may be embodied in composition.
Adhesive may include but be not limited to cellulose, methylcellulose, hydroxymethyl cellulose, calcium carboxymethylcellulose, carboxylic
Sodium carboxymethylcellulose pyce, hydroxypropyl cellulose, HPMCP, noncrystalline cellulose, polyethylene pyrrole noise made in coughing or vomiting
Alkanone, polyvinylpyrrolidone (PVP, PVP), gelatin, Arabic gum and gum arabic, polyethylene glycol, starch, sugar are all
Such as sucrose, kaolin, glucose and lactose, cholesterol, bassora gum, stearic acid, gelatin, casein, lecithin (phosphatide), 18
Hexadecanol, cetanol, cetyl esters wax, dextrin, glucan, glyceryl monooleate, glycerin monostearate, glyceryl palmito
Acyl stearate, polyoxyethylene alkyl ether, castor oil derivatives, Myrj 45, polyvinyl alcohol, gelatin
Deng.
Lubricant may include silicic acid anhydride, talcum, stearic acid, NaLS, magnesium stearate and stearoyl-fumarate
Sodium etc..
Granulating agent may include but be not limited to silica, starch, calcium carbonate, pectin, Crospovidone and PVPP.
Disintegration reagent or disintegrant may include but be not limited to starch, carboxymethyl cellulose, the hydroxypropyl cellulose of substitution, carbon
Sour hydrogen sodium, calcium phosphate, calcium citrate, Sodium Starch Glycolate, pregelatinized starch or Crospovidone.
Emollient may include but be not limited to stearyl alcohol, ermine oil, cetanol, oleyl alcohol, isopropyl laurate, polyethylene glycol, olive
Olive oil, vaseline, palmitic acid, oleic acid and myristyl myristate.
Surfactant may include but be not limited to polysorbate, sorbitan ester, poloxamer or lauryl sulfate
Sodium.
Metal-chelator may include but be not limited to physiologically acceptable chelating agent, and it includes ethanedioic acid, malic acid or richness
Horse acid.
The pH in dry or liquid form composition with about 5.5 to about 6.5 as described herein.PH adjusting agent can be used for
PH comprising the solution that Buddhist nun is replaced according to Shandong is adjusted to about 6.PH adjusting agent may include but be not limited to citric acid, ascorbic acid, rich horse
Acid, malic acid, hydrochloric acid, sodium hydroxide, their salt or combinations thereof.
E. the stability of composition
Nylon 6 combination is replaced according to Shandong as described herein, no matter in solid form or liquid form, (i.e. pH is in neutrallty condition
About 6 to being stable under about 8).The composition is also stable under light illumination.In one embodiment, for not
For the sample stored under synthermal and humidity, the composition is stable within the period of about 1 hour.Such as this paper institutes
With term stably refers to composition degraded less than about 3% as described herein.In one embodiment, the composition is about
It is stable under 20 DEG C/50% relative humidity to about 45 DEG C/75% relative humidity.In another embodiment, it is described herein
Composition for or greater than about 25 DEG C at a temperature of and be or greater than about 60% relative humidity under, more than 1 month when
Between degraded less than about 3% in section.
When the medicament with semi-solid or liquid mixes, the solid composite is also stablized at least about 6 hours.In a reality
Apply in scheme, the solid composite can be suspended in liquid or semisolid and disperse again after 6 hours.In another reality
Apply in scheme, stable up to about 6 hours of the solid composite being suspended in liquid or semisolid.
Stability can be monitored by a variety of methods as known in the art.In one embodiment, observable capsule
Any physics aspect or color change are detected with liquid.In one embodiment, capsule color change or the modification of capsule
The degraded or deterioration of capsule are may indicate that, so as to influence security or effect.
Composition as described herein can store at the temperature of reduction, room temperature or selected temperature.In an embodiment
In, composition is stored at a temperature of about 0 to about 10 DEG C.In another embodiment, composition is stored in about 2 to about 8 DEG C
At a temperature of.The composition can store in the case of in the absence of water, air and moisture.However, except atmospheric conditions, in room
The lower storage of temperature does not influence the general stability of composition.
F. the method for using the composition
The method that according to Shandong Buddhist nun will be replaced to be delivered to patient is also provided, wherein methods described includes giving composition as described herein
Medicine is in patient.Therefore, the composition can be used for treating or preventing illness.In some embodiments, illness is to be listed in the U.S.
Those in patent 8,497,277,8,476,284,8,703,780 and 8,754,090, the patent document is by reference simultaneously
Enter herein.
The composition can be used for treatment with one or more subjects in any illness illustrated herein.It is described
Composition can also be useful in terms of prevention, i.e., described composition can deliver medicine to easily to be influenceed or otherwise by malignant tumour
The patient of risk in development malignant tumour.The composition can be additionally used in maintaining treatment, that is, deliver medicine in the paracmasis
Patient.
In certain embodiments, methods described includes treating one or more autoimmune diseases.In an implementation
In scheme, autoimmune disease is IBD, arthritis, lupus, rheumatoid arthritis, psoriatic arthritis, bone
Arthritis, still's disease, adolescent arthritis, diabetes, myasthenia gravis, Hashimoto thyroiditis, Ao Erde thyroiditis,
Graves disease, Sjogren syndrome, multiple sclerosis, acute diseminated encephalomyelitis, Ai Disheng syndromes, rigid spine
Inflammation, antiphospholipid antibody syndrome, alpastic anemia, oneself immunity hepatitis, chylous diarrhea, Goodpaster syndrome, spy
Hair property thrombocytopenic purpura, optic neuritis, chorionitis, PBC, Reiter syndrome, high sheep artery
It is inflammation, temporal arteritis, warm autoimmune hemolytic anemia, Wegner's granulomatosis, psoriasis, whole body alopecia, Behcet's disease, slow
Fatigue, insomnia, endometriosis, interstitial cystitis, Neuromuscular sarcoma, chorionitis or Vulvodynia.
In other embodiments, methods described includes treating one or more heteroimmunity diseases.In an implementation
In scheme, heteroimmunity disease be graft versus host disease(GVH disease), transplanting, blood transfusion, allergic reaction, allergy, the hypersensitivity of I types,
Allergic conjunctivitis, allergic rhinitis or atopic dermatitis.
In certain embodiments, methods described includes treating one or more diseases associated with inflammation.In an embodiment
In, diseases associated with inflammation be arthritis, asthma, appendicitis, blepharitis inflammation, capillary bronchitis, bronchitis, bursal synovitis, cervicitis,
Cholangitis, cholecystitis, colitis, conjunctivitis, cystitis, dacryocystitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometrium
Inflammation, enteritis, enterocolitis, epicondylitis, epididymitis, fascitis, fiber device inflammation, gastritis, gastroenteritis, hepatitis, suppurative nettle
Rash, laryngitis, mastitis, meningitis, myelitis myocarditis, myositis, ephritis, oaritis, orchitis, osteitis, otitis, pancreatitis,
Parotitis, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, pneumonitis, pneumonia rectitis, prostatitis, renal plevis kidney
Inflammation, rhinitis, salpingitis, nasosinusitis, stomatitis, synovitis, tendonitis, tonsillitis, uveitis, vaginitis, vasculitis or
Vulvitis.
In other embodiments, methods described includes treating one or more cancers.In one embodiment, it is described
Cancer is B cell proliferation disease.In another embodiment, the cancer is hematologic malignancies.In another implementation
In scheme, cancer is B cell lymphocytic leukemia, leukaemia, lymthoma, lymphoproliferative diseases, lymphoplasmacytic
Property lymthoma, Wa Erdengshi macroglobulinemias, myelopathy, plasma cell myeloma, plasmacytoma, mediastinum large B cell lymphoid tumor,
Intravascular large B cell lymphoma, primary sepage lymthoma, lymphomatoid granulomatosis, NHL CLL, SLL,
It is excessive risk CLL, non-CLL/SLL lymthomas, follicular lymphoma, diffusivity large B cell lymphoid tumor, lymphoma mantle cell, multiple
It is myeloma, marginal zone lymphoma, non-primary base spy high-grade B cell lymphoma, extranodal marginal zone B cell lymphoma, acute or chronic
Granulocytic leukemia, myelodysplastic syndrome, lymphocytic leukemia, recurrent or intractable diffusivity large B cell
Lymthoma, recurrent or intractable lymphoma mantle cell, recurrent or intractable follicular lymphoma, recurrent or intractable
CLL, recurrent or intractable SLL, relapsed or stubborn Huppert's disease, Burkitt lymphoma, cutaneous B-cell lymphoma,
The small excision cell of cutaneous marginal zone lymphomas lymthoma, diffusivity mixing smallcelllymphoma, diffusivity, the small incising cell of the outer folliculus of knot,
The small cutting of folliculus mixing and maxicell, folliculus maxicell, intravascular lymthoma, maxicell immunoblastic lymphoma, maxicell
Lymthoma, lymphoma mucosa associated lymphoid tissue, immunocyte large celllymphoma, precursor B lymphocytic lymphoma, chronic leaching
Bar chronic myeloid leukemia/small lymphocyte lymthoma, lymphoma nodal marginal zone B cell, Splenic marginal zone B-cell lymphoma, original
Hair property mediastinal B-cell lymphoma, hairy cell leukemia and primary central nervous system lymphoma.In another embodiment
In, the B cell proliferation disease be NHL, macroglobulinemia Waldenstron, plasma cell myeloma,
Or chronic lymphocytic leukemia.In another embodiment, B cell proliferation disease is diffusivity large B cell lymph
Knurl, follicular lymphoma, lymphoma mantle cell and Burkitt lymphoma.In another embodiment, the cancer is leukaemia.
In another embodiment, the cancer is lymthoma.
In other embodiments, methods described includes treatment thromboembolic disorders.In one embodiment, thrombus bolt
Plug disease is miocardial infarction, angina pectoris, postangioplasty occlusion, postangioplasty restenosis, aortocoronary again
Shunting again occlusion, aortocoronary bypass restenosis, apoplexy, Temporary ischemia, periphery artery occlusion obstacle, pulmonary embolism or
DVT.
According to Shandong for the dose requirements of Buddhist nun can be based on the symptom of presentation seriousness and the specific subject that is treating and
It is different.Treatment can be by the low dose less than the optimal dose that Buddhist nun is replaced according to Shandong.Hereafter, can incremental dose until realize ring
Optimum efficiency under border.Accurate dosage will be determined by attending doctor based on the experience of treated individual subject.
In one embodiment, the composition is will provide effective result but not cause any unacceptable harmful or harmfulness pair
The concentration administration of effect.
As used herein, term " effective dose " refers to that the institute of one or more symptoms of B cell proliferation disease will be alleviated
The medicament of administration or the sufficient amount of compound.The result can reduce and/or mitigate the symptom, symptom or the origin cause of formation of disease.At certain
In a little embodiments, effective dose realizes the amount that desired pharmacological action or treatment improve without excessive adverse side effect.
According to Shandong for Buddhist nun effective dose can according to the component of composition, the pattern of delivering, the seriousness for the illness treated,
The age of patient and weight and different for any other active component in composition.It can also adjust to prescription
Case is to provide optimal therapeutic response.Several fractionated doses can be delivered daily, such as with daily 2 to 4 deliverings of divided doses, or
Single dosage can be delivered.However, the dosage proportional can decrease or increase, as indicated by the state of emergency as treatment
's.In one embodiment, delivering is based on daily, weekly or monthly.In another embodiment, delivering is based on passing daily
Send.The composition can daily administration.In some embodiments, the composition can every other day be administered.In some implementations
In scheme, the composition can be administered once a day or repeatedly.In some embodiments, the composition can be given daily
Medicine is two or more times.In some embodiments, the composition can be with daily administration three times or more.
The dosage can also be based on periodically delivering and reduce or raise.Attending doctor also have continue it is identical administration one when
Between section flexibility or can determine change administration time table.This is probably composition unfavorable but not due to improved illness
Fatal reaction etc..If stopping administration, if patient is stable or the improvement of illness has been carried out, can continue again to
Medicine.Therefore, the dosage of administration, frequency or combinations thereof decrease or increase as needed.
According to Shandong for Buddhist nun dosage can according to the seriousness of disease, the weight of subject, subject age etc. no
Together.In one embodiment, effective dose is about 0.1 to about 5000mg/ days.In one embodiment, the having for Buddhist nun according to Shandong
Effect amount is about 1 to about 1500mg/ days.In another embodiment, it is about 20 to about 450mg/ days for the effective dose of Buddhist nun according to Shandong.
In a further embodiment, it is about 20 to about 420mg/ days for the effective dose of Buddhist nun according to Shandong.In another embodiment, according to Shandong
Effective dose for Buddhist nun is about 30 to about 300mg/ days.In a further embodiment, it is about 50 to about for the effective dose of Buddhist nun according to Shandong
200mg/ days.In another embodiment, it is about 70 to about 140mg/ days for the effective dose of Buddhist nun according to Shandong.
Desired dosage can be provided easily with single dose, or simultaneously (or in a short time) or with appropriate interval,
Such as the fractionated dose that two, three, four, or more sub-doses/day is applied provides.
The composition can be delivered to subject by any appropriate path, as instructed as attending doctor.One
In individual embodiment, the composition oral delivering.
The composition can also be administered altogether with one or more second medicaments.Second medicament can be in composition as described herein
Before, it is administered simultaneously or afterwards.In some embodiments, the second medicament includes chemotherapeutic, steroids, immunization therapy
Medicament etc..In another embodiment, second medicament is one of the following or a variety of:D actinomycin D, alkylating agent, AVM hereinafter
A acid, hemel, Ah 'ss deforestation, anagrelide, angiogenesis inhibitors, antibody, antiandrogen, antiestrogenic, antimetabolic
Medicine, anthracycline antibiotic, arsenic trioxide, L-Asparaginasum, B-cell receptor pathway inhibitor (CD79A inhibitor, CD79B suppressions
Preparation, CD19 inhibitor, Lyn inhibitor, Syk inhibitor, PI3K inhibitor, Blnk inhibitor, PLCy inhibitor, PKCP suppress
Agent), basiliximab, bexarotene, bortezomib, Calcineurin inhibitors, kanamycins, celecoxib,
Ceradenovec, colchicine derivative, cytotoxic antibiotics, up to for pearl monoclonal antibody, denileukin diftitox, DNA
Damage agent, epoxides, Estramustine, estrogen, aziridine, folacin, gonadotropin releasing hormone interferon, growth
The factor, hdac inhibitor, Hedgelog protein inhibitor, Hsp90 inhibitor, histone deacetylase inhibitor, hormone, hormone are similar
Thing, hormone antagonist, hydroxycarbamide, IAP inhibitor, Yi Buta pearl monoclonal antibodies immunostimulant, immunodepressant, interleukins suppression
Preparation, interleukins, Irinotecan, Jakl/2 inhibitor, rhodamine amine, horse rope POLO, meter Bo Zhu monoclonal antibodies, rice spy lucky star,
Rice support guanidine, mitotane, monoclonal antibody, mTOR inhibitors, methyl hydrazine, mustargen, nitroso ureas, PI3K inhibitor, oblimersen,
PARP inhibitor, Pegaspargase, Pentostatin, pkc inhibitor, plant alkaloid, platinum compounds (carboplatin, cis-platinum, oxaliplatin
Or Satraplatin), podophyllotoxin derivative, progestational hormone, proteasome inhibitor, kinases inhibitor, protease inhibitors, purine
Analog, pyrimidine analogue, RIT agent, sensitizer, sieve for Qusong, west for plus woods, diazonium furans, TPT,
Tretinoin, TNF, TNF-α inhibitor, trastuzumab, telomerase inhibitor, for Nai Meiding, Tosi not triamine, excellent spy
Gram monoclonal antibody, vinca alkaloids or Vorinostat amine.In another embodiment, second medicament includes adriamycin, more mildews
Element, bleomycin, vincaleukoblastinum, cis-platinum, Acivicin, Aclarubicin, hydrochloric acid acodzole, Aclarubicin, Adozelesin, A Di
Interleukin, alemtuzumab, hemel, ambomycin, isopropyl acetate, aminoglutethimide, amsacrine, Anastrozole, ammonia fennel are mould
Element, asparaginase, asperline, azacitidine, Azetepa, azotomycin, Batimastat, bendamustine, shellfish cut down list
Anti-, Benzodepa, Bicalutamide, Bisantrene Hydrochloride, bisnafide, Bizelesin, sulfuric acid bleomycin, brequinar sodium, bromine
Found bright, busulfan, D actinomycin D, Calusterone, Caracemide, Carbetimer, carboplatin, BCNU, Carminomycin Hydrochloride, card
Folding comes new, Cedefingol, Cetuximab, Chlorambucil, Cirolemycin, Cladribine, crisnatol, gram azoles for Buddhist nun, ring
Prick croak phosphamide, cytarabine, Dacarbazine, daunorubicin hydrochloride, Decitabine, Dexormaplatin, Dezaguanine, methanesulfonic acid
Rather, Aziridinyl Benzoquinone, adriamycin, doxorubicin hydrochloride, Droloxifene, citric acid Droloxifene, Masterone, duazomycin,
Edatrexate, fenoperic acid hydrochloride, Elsamitrucin, Enloplatin, enpromate, Epipropidine, epirubicin hydrochloride, E Buluo
Azoles, esorubicin hydrochloride, Estramustine, estramustine phosphate sodium, etanidazole, Etoposide, etoposide phosphate, Ai Tuobu
Rather, hydrochloric acid method bends azoles, fazarabine, Suwei A amine, floxuridine, fludarabine phosphate, fluorouracil, fluorocitabine, 5-
Fluorouracil, Fosquidone, Fostriecin sodium, gemcitabine, gemcitabine hydrochloride, gemtuzumab, hydroxycarbamide, hydrochloric acid she reach than
Star, ifosfamide, ilmofosine, interleukin I I, Intederon Alpha-2a, Interferon Alpha-2b, interferon alfa-n1, Alferon N,
Interferon beta-1a, gamma interferon 1-b, iproplatin, irinotecan hydrochloride, lanreotide acetate, Letrozole, leuprorelin acetate, salt
Sour Liarozole, lometrexol sodium, lomustine, losoxantrone hydrochloride, Masoprocol, maytansine, mustine hydrochlcride, tumer
Progesterone, melengestrol acetate, melphalan, menogaril, mercaptopurine, methotrexate (MTX), methotrexate sodium, metoprine, U.S. appropriate replace
Piperazine, mitindomide, rice support jinx, mitocromin, Mitogillin, mitomalcin, mitomycin, mitosper, mitotane, hydrochloric acid
Mitoxantrone, mycophenolic acid,Nocodazole, nogalamycin, difficult to understand, Ormaplatin, Oxisuran, Japanese yew
Alcohol, Pegaspargase, Peliomycin, pentamustine, peplomycin sulfate, Perfosfamide, pipobroman, A-20968, hydrochloric acid pyrrole sieve anthracene
Quinone, mithramycin, Plomestane, Porfimer Sodium, porphyromycin, prednimustine, Procarbazine Hydrochloride, puromycin, salt
Sour puromycin, pyrazofurin, riboprine, Rituximab, Rogletimide, Safingol, hydrochloric acid Safingol, methyl ring
Own Nitrosourea, simtrazene, sparfosate sodium, sparsomycin, spirogermanium hydrochloride, spiromustine, Spiroplatin,
Streptonigrin, streptozotocin, Sulofenur,Talisomycin,Tecogalan sodium, tegafur, hydrochloric acid
Teloxantrone, Temoporfin, Temozolomide, Teniposide, teroxirone, testolactone, thiapurine, thioguanine, thiotepa,
Riboxamide, Tirapazamine, Toremifene Citrate, acetic acid Trestolone, Triciribine Phosphate, Trimetrexate, front three are bent
Husky glucuronic acid fat, Triptorelin, tubulozole hydrochloride,Uracil mustard, uredepa, Vapreotide, dimension are for pool
Sweet smell, vinblastine sulfate, vincristine sulfate, desacetyl vinblastine amide,
Vindesine Sulfate, sulfuric acid vinepidine, sulfuric acid vinglycinate, vinleurosine sulfate,
It is vinorelbine tartrate, vinrosidine sulfate, sulfuric acid vinzolidine, Vorozole, wortmannin, Zeniplatin, net
Si Tading, zorubicin hydrochloride.
G. the kit of composition is included
Also provide comprising according to optional carrier of the Shandong for Buddhist nun and suitable for delivering medicine to mammalian subject as described above
Kit or packaging.In one embodiment, capsule can be packaged in bottle, cover plate packaging, pillbox etc..In another reality
Apply in scheme, liquid preparation can be packaged in the bottle for being optionally coated with that cap, ampoule, drop recorder can be punctured or in bag of saline.
Kit or packaging comprising composition as described herein are designed in method described herein.Kit
Also optionally include for apply composition, the carrier suitable for applying said compositions, one or more instruments (including but
Be not limited to syringe, pipettor, clamp, measuring spoon etc.) explanation.Other components included in kit are to people in the art
It will be apparent for member, while in view of desired instruction and delivering mode.
The following example is provided to show heretofore described part concept.Although each embodiment is considered as and provides one
Individual specific single composition embodiment, or the method for preparing and using, but all embodiments are not regarded as being limited to this
More common embodiment described in text.
In certain embodiments, make efforts to ensure the accuracy of digital (such as amount, temperature etc.) used, but should examine
Consider some experimental errors and deviation.Except as otherwise noted, temperature by DEG C in units of, pressure is in or near atmospheric.
Embodiment
Embodiment 1:Include the solid composite that Buddhist nun is replaced according to Shandong
Prepare comprising the solid composite that Buddhist nun is replaced according to Shandong, it is to contain in capsule, as described below.
A.140mg capsule
In the method, blend passes through in a reservoir by MCC (151.49mg in particle;Avicel PH 101)、SLS
(9.40mg;Kolliphor;It is fine) and CCS (13.10mg;Ac-di-sol) mix to prepare.Then, can be by it with being replaced according to Shandong
Buddhist nun (70mg, micronizing, Lonza, Nansha) mixing.Then add it is remaining according to Shandong for Buddhist nun (70mg) and composition being mixed
Close.Then, by magnesium stearate (0.8mg;Non-Bovine#5712) add in the mixture, and said mixture is blended
To provide pre- roll-in blend.Then, by pre- roll-in blend roll-in to form ribbon.Then by the ribbon grind with
The composition for including particle is provided.
Then the SLS (4.6mg, Kolliphor, fine) and CCS (9.9mg, Ac-di- of the particle and Part II
Sol) it is blended.Then the magnesium stearate (0.8mg, Non-Bovine#5712) of Part II is added into blend to provide profit
Sliding blend.Then the blend of the lubrication is added in No. 0 Sweden's orange hard gelatin capsule.
B.50mg Buddhist nun's capsule is replaced according to Shandong
In the method, in particle blend by by MCC (54.07mg;Avicel PH101)、SLS(3.36mg;
Kolliphor;It is fine) and CCS (4.68mg;Ac-di-sol) mix to prepare.Then, can by this with according to Shandong for Buddhist nun (25mg,
Micronizing, Lonza, Nansha) mixing.Then add it is remaining according to Shandong for Buddhist nun (25mg) and composition being mixed.Then,
By magnesium stearate (0.29mg;Non-Bovine#5712) add in the mixture, and said mixture blending is pre- to provide
Roll-in blend.Then, by pre- roll-in blend roll-in to form ribbon.Then the ribbon is ground and included with providing
The composition of particle.
Then the SLS (1.64mg, Kolliphor, fine) and CCS (3.54mg, Ac-di- of the particle and Part II
Sol) it is blended.Then magnesium stearate (0.29mg, Non-Bovine#5712) is added into blend to provide the blending of lubrication
Thing.Then the blend (117.87mg) of the lubrication is separately added No. 0 Sweden's orange hard gelatin capsule and Sweden's orange spray paste
In capsule.
Embodiment 2:Include the liquid suspension compositions that Buddhist nun is replaced according to Shandong
(i) 70mg/mL replaces Buddhist nun's liquid suspension according to Shandong
Prepare the fluid composition that Buddhist nun is replaced according to Shandong comprising 70mg/mL.Specifically, by water (300mL) and CCS composition
MCC(Avicel RC591;6.5g) mix and continue 30 minutes.Then useHomogenizer is with maximal rate
The dispersion is homogenized 30 seconds by (7500rpm).Using magnetic stirring apparatus by HPMC (29105mPas;1.25g) with water (120mL)
Mixing is until uniformly.Then it will be micronized and add in HPMC solution and mix 120 for Buddhist nun (35g, Lonza Clinical) according to Shandong
Minute.Then MCC/CCS dispersions are mixed with according to Shandong for Buddhist nun's mixture.By Sucralose (0.5g), P-hydroxybenzoic acid first
Ester sodium (0.5725g) and nipagin A sodium (0.2875g) are added in mixture., will after stirring in about 10 minutes
Citric acid monohydrate compound (0.7565g) and parenteral ADSP (0.69g) are added in the mixture.Mixture is stirred
Mix about 10 minutes until content solubilising.Measure the pH of mixture and be found to be 5.99, so as to eliminate regulation pH needs.So
Afterwards with the water diluted mixture of purifying until final weight is 510.5g.Mixture is measured again and is found to be about 6.
The concentration of every kind of component in final fluid composition is provided in table 2.
(ii) 40mg/mL replaces Buddhist nun's liquid suspension according to Shandong
Prepare the fluid composition that Buddhist nun is replaced according to Shandong comprising 40mg/mL.Specifically, by water (300mL) and CCS composition
MCC(Avicel RC591;7g) mix and continue 30 minutes.Then useHomogenizer is with maximal rate
The dispersion is homogenized 30 seconds by (7500rpm).Using magnetic stirring apparatus by HPMC (2910 5mPas;0.5g) with water (120mL)
Mixing is until uniformly.Then it will be micronized and add in HPMC solution and mix 120 for Buddhist nun (20g, Lonza Clinical) according to Shandong
Minute.Then MCC/CCS dispersions are mixed with according to Shandong for Buddhist nun's mixture.By Sucralose (0.25g), P-hydroxybenzoic acid first
Ester sodium (0.6791g) and nipagin A sodium (0.3387g) are added in mixture., will after stirring in about 10 minutes
Citric acid monohydrate compound (0.801g) and parenteral ADSP (0.69g) are added in the mixture.Mixture is stirred
Mix about 10 minutes until content solubilising.Measure the pH of mixture and be found to be about 5.99, so as to eliminate regulation pH needs.
Then with the water diluted mixture of purifying until final weight is 507g.Then by mixture homogenization.PH is measured again and is sent out
It is now about 6.
The concentration of every kind of component in final fluid composition is provided in table 3.
Embodiment 3:Comprising the extensive preparation according to Shandong for the suspension of Buddhist nun, 4L batches are prepared
The water (480g) of purifying is added in container and is heated to about 83 DEG C with about 400rpm stir speed (S.S.) and holds
Renew a contract 60 minutes.HPMC (10.002g) is slowly added in container and mixture is divided with about 7600rpm speed stir about 4
Clock is until mixture homogenization.Purified water (480g) is added to the container and then will be mixed with about 500rpm speed at room temperature
Compound stir about 5 minutes is until mixture solubilising.Will according to Shandong for Buddhist nun (278.6g) add mixture in, and with 600rpm by its
Stir about 2h is until its homogenizing.Use the aggregate of microscope monitoring mixture.
Then, purified water (2400g) is added in second container.With about 500rpm speed, within the period of 3 minutes
MCC (51.74g, Avicel) is added in second container, afterwards with about 400rpm speed stir about 60 minutes.Then about 4
In the period of minute, using about 7600tr/min stir speed (S.S.), by the mixture homogenization.Mixture is monitored using microscope
Aggregate.
Then, the mixture in the first container is added in the mixture in second container, and with about 500rpm speed
The content of mixing is stirred and lasts about 5 minutes by degree.Then, using purified water (200ml) rinse the first container, and by its
Add in second container.Under medium stirring condition, by Sucralose (4.0038g), Sodium Methyl Hydroxybenzoate
(4.5838g) and nipagin A sodium (2.300g) are sequentially added in second container and stir the mixture for about 11
Minute is until solid solubilising.Then, citric acid monohydrate compound (6.052g) is added in second container and stirred the mixture for
About 10 minutes.Then add anhydrous slufuric acid disodium hydrogen (5.521g) and stir the mixture for about 10 minutes until content increases
It is molten.Measure the pH of solution and be found to be about 5.94, so as to eliminate regulation pH needs.
Then using water (4064g) diluted mixture of purifying until final weight is 4084g.Then it is mixture is equal
Change.PH is measured again and is found to be about 5.98.Then within the period of about 75 minutes, with about 500 to about 1300rpm speed
Degree removes the aliquot (8ml) of mixture under constant stirring.Each aliquot is added to amber vial
In (10ml), then by rubber injection plug (20mm) the insertion bottle of Flurotec coatings, and the plug aluminum is torn
Draw lid (20mm) fixed.Referring to Fig. 3.
Embodiment 4:The stability study of Buddhist nun's preparation is replaced according to Shandong
Evaluate stability of the solid composite as described herein in 3 kinds of liquid.Specifically, at room temperature, by this paper institutes
The content (each self-contained 140mg solid composite) of state 4 kinds sprinkling capsules be dissolved in water (100mL), milk (100mL) and
In orange juice (100mL).After about 6 hours, the color keep of milk and orange juice solution is constant, but the aqueous solution becomes milky white
Color.
Using liquid chromatogram find three kinds according to Shandong for Buddhist nun's preparation be stable.Specifically, after stirring 6 hours, from this
There are the most of of trace impurity to replace Buddhist nun's activating agent according to Shandong for recovery in a little preparations.
Embodiment 5:Studied using according to Shandong for the feeding tube of Buddhist nun's preparation
Feasibility study is carried out to feeding tube using composition as described herein.Specifically, two kinds of preparations, every kind of preparation are prepared
Include the content (the active equivalents particle for being total up to 560mg) of the sprinkling capsule as described herein of water (20mL) and 4 kinds.Make system
When agent by size is 2.2mm and 2.7mm ID feeding tubes, it was observed that the preparation (including water and composition) due to gravity and
Pass through pipe with not blocking.
It has also been found that before other preparations are introduced, the reusable pipe.Specifically, applied by using syringe few
Pressure is measured, blows air over pipe.Then in the case of no any interruption additional formulations can be made to pass through pipe.Though it should be appreciated that
Its preferred embodiment is combined in right description of the invention, but embodiment described above and thereafter is only intended to
Illustrate the scope being not intended to limit the present invention.It will be apparent to one skilled in the art that can without departing from the scope of the invention,
Carry out a variety of changes and substituted with equivalent, and other side, advantage and the modification of the present invention will be to this hairs
Bright those skilled in the art is obvious.In addition to the embodiment described herein, the present invention is envisioned and wanted
Ask invention that feature of the invention cited herein is drawn after combining and cited be used to supplement showing for feature of present invention
There is the right for the invention that Technical Reference document drawn.Similarly, it will be appreciated that described material, feature or product can be with appointing
What other materials, feature or product are used in combination, and such combination is fallen within the scope of the present invention.
It is cited herein or description each patent, patent application and patent disclose in disclosure, no matter for what
Kind purpose, is incorporated by herein.
Claims (66)
1. a kind of pharmaceutical composition, described pharmaceutical composition include according to Shandong for Buddhist nun, its salt, prodrug or metabolin, microcrystalline cellulose,
Ac-Di-Sol, NaLS and magnesium stearate.
2. pharmaceutical composition according to claim 1, described pharmaceutical composition include about 40 to about 45 weight % according to Shandong
For Buddhist nun.
3. pharmaceutical composition according to claim 1 or 2, described pharmaceutical composition includes about 50 to about 140mg according to Shandong
For Buddhist nun.
4. pharmaceutical composition according to any one of claim 1 to 3, described pharmaceutical composition includes about 44 to about 47 weights
Measure % microcrystalline cellulose.
5. pharmaceutical composition according to any one of claim 1 to 4, described pharmaceutical composition includes about 6 to about 8 weights
Measure % Ac-Di-Sol.
6. pharmaceutical composition according to any one of claim 1 to 5, described pharmaceutical composition includes about 3 to about 5 weights
Measure % intra-particle crosslink sodium carboxymethylcellulose.
7. pharmaceutical composition according to any one of claim 1 to 6, described pharmaceutical composition includes about 2 to about 4 weights
Measure % extragranular connection sodium carboxymethylcellulose.
8. pharmaceutical composition according to any one of claim 1 to 7, described pharmaceutical composition includes about 1 to about 5 weight
Measure % NaLS.
9. pharmaceutical composition according to claim 8, described pharmaceutical composition includes about 2.5 to about 3 weight % particle
Interior NaLS.
10. pharmaceutical composition according to claim 8 or claim 9, described pharmaceutical composition includes about 1.2 to about 1.6 weight %
The outer NaLS of particle.
11. pharmaceutical composition according to any one of claim 1 to 10, described pharmaceutical composition includes about 0.4 to about
0.6 weight % magnesium stearate.
12. the pharmaceutical composition according to any one of claim 1 to 11, described pharmaceutical composition includes about 0.45 to about
0.5 weight % magnesium stearate.
13. the pharmaceutical composition according to any one of claim 1 to 12, described pharmaceutical composition includes about 0.2 to about
Magnesium stearate in 0.3 weight % particle.
14. the pharmaceutical composition according to any one of claim 1 to 13, described pharmaceutical composition includes about 0.2 to about
0.3 weight % extragranular magnesium stearate.
15. pharmaceutical composition according to claim 1, described pharmaceutical composition includes material in particle, in the particle
Material is included according to Shandong for Buddhist nun, its salt, prodrug or metabolin, microcrystalline cellulose, Ac-Di-Sol, NaLS
And magnesium stearate.
16. the pharmaceutical composition according to claim 1 or 15, described pharmaceutical composition includes the outer material of particle, described
The outer material of grain includes Ac-Di-Sol, NaLS and magnesium stearate.
17. a kind of pharmaceutical composition, described pharmaceutical composition include:
(i) about 40 to about 45 weight % according to Shandong replace Buddhist nun;
(ii) about 44 to about 47 weight % microcrystalline cellulose;
(iii) about 6 to about 8 weight % Ac-Di-Sol;
(iv) about 1 to about 5 weight % NaLS;With
(v) about 0.2 to about 0.3 weight % magnesium stearate.
18. a kind of pharmaceutical composition, described pharmaceutical composition include:
(i) about 140mg according to Shandong replaces Buddhist nun;
(ii) about 151mg microcrystalline cellulose;
(iii) about 23mg Ac-Di-Sol;
(iv) about 14mg NaLS;With
(v) about 1.6mg magnesium stearate.
19. pharmaceutical composition according to claim 18, wherein the Ac-Di-Sol includes about 13mg's
Intra-particle crosslink sodium carboxymethylcellulose and about 9.9mg extragranular connection sodium carboxymethylcellulose.
20. pharmaceutical composition according to claim 18, wherein the NaLS is included in about 9.4mg particle
The outer NaLS of NaLS and about 4.6mg particle.
21. pharmaceutical composition according to claim 18, wherein the magnesium stearate includes tristearin in about 0.8mg particle
Sour magnesium and about 0.8mg extragranular magnesium stearate.
22. a kind of pharmaceutical composition, described pharmaceutical composition include:
(i) about 50mg according to Shandong replaces Buddhist nun;
(ii) about 54mg microcrystalline cellulose;
(iii) about 8mg Ac-Di-Sol;
(iv) about 5mg NaLS;With
(v) about 0.6mg magnesium stearate.
23. pharmaceutical composition according to claim 22, wherein the Ac-Di-Sol includes about 4.6mg's
Intra-particle crosslink sodium carboxymethylcellulose and about 3.5mg extragranular connection sodium carboxymethylcellulose.
24. pharmaceutical composition according to claim 22, wherein the NaLS is included in about 3.3mg particle
The outer NaLS of NaLS and about 1.6mg particle.
25. pharmaceutical composition according to claim 22, wherein the magnesium stearate includes tristearin in about 0.3mg particle
Sour magnesium and about 0.3mg extragranular magnesium stearate.
26. a kind of capsule, the capsule includes the pharmaceutical composition according to any one of claim 1 to 25.
27. capsule according to claim 26, the capsule is gelatine capsule.
28. the capsule according to claim 26 or 27, the capsule is hard gelatin capsule.
29. the capsule according to any one of claim 26 to 28, the capsule is standard or sprinkling capsule.
30. the capsule according to any one of claim 26 to 29, the capsule is Sweden's orange capsule.
31. the capsule according to any one of claim 26 to 30, the capsule is No. 0 capsule.
32. a kind of pharmaceutical composition, described pharmaceutical composition is included according to Shandong for Buddhist nun, its salt, prodrug or metabolin, microcrystalline cellulose
Element, sodium carboxymethylcellulose, hydroxypropyl methyl cellulose, citric acid monohydrate compound, disodium hydrogen phosphate, Sucralose, to hydroxyl
Methyl benzoate sodium, nipagin A sodium, concentrated hydrochloric acid, sodium hydroxide and water.
33. pharmaceutical composition according to claim 32, described pharmaceutical composition includes about 30 to about 80mg/mL according to Shandong
For Buddhist nun.
34. the pharmaceutical composition according to claim 32 or 33, described pharmaceutical composition includes about 30 to about 50mg/mL's
Buddhist nun is replaced according to Shandong.
35. pharmaceutical composition according to claim 32, described pharmaceutical composition includes about 60 to about 80mg/mL according to Shandong
For Buddhist nun.
36. the pharmaceutical composition according to any one of claim 32 to 35, described pharmaceutical composition includes about 12 to about
15mg/mL microcrystalline cellulose and sodium carboxymethylcellulose.
37. the pharmaceutical composition according to any one of claim 32 to 36, described pharmaceutical composition includes about 13 to about
15mg/mL microcrystalline cellulose and sodium carboxymethylcellulose.
38. the pharmaceutical composition according to any one of claim 32 to 37, described pharmaceutical composition includes about 12 to about
14mg/mL microcrystalline cellulose and sodium carboxymethylcellulose.
39. the pharmaceutical composition according to any one of claim 32 to 38, described pharmaceutical composition includes about 0.5 to about
3mg/mL hydroxypropyl methyl cellulose.
40. the pharmaceutical composition according to any one of claim 32 to 39, described pharmaceutical composition includes about 2 to about
3mg/mL hydroxypropyl methyl cellulose.
41. the pharmaceutical composition according to any one of claim 32 to 40, described pharmaceutical composition includes about 0.5 to about
1.5mg/mL hydroxypropyl methyl cellulose.
42. the pharmaceutical composition according to any one of claim 32 to 41, described pharmaceutical composition includes about 1.4 to about
1.7mg/mL citric acid monohydrate compound.
43. the pharmaceutical composition according to any one of claim 32 to 42, described pharmaceutical composition includes about 1.4mg/
ML disodium hydrogen phosphate.
44. the pharmaceutical composition according to any one of claim 32 to 43, described pharmaceutical composition includes about 0.5 to about
1.5mg/mL Sucralose.
45. the pharmaceutical composition according to any one of claim 32 to 44, described pharmaceutical composition includes about 1 to about
1.5mg/mL Sodium Methyl Hydroxybenzoate.
46. the pharmaceutical composition according to any one of claim 32 to 45, described pharmaceutical composition includes about 0.5 to about
0.7mg/mL nipagin A sodium.
47. the pharmaceutical composition according to any one of claim 32 to 46, described pharmaceutical composition includes enough dense
Hydrochloric acid is to maintain about 6 pH.
48. the pharmaceutical composition according to any one of claim 32 to 47, described pharmaceutical composition includes enough hydrogen
Sodium oxide molybdena is to maintain about 6 pH.
49. the pharmaceutical composition according to any one of claim 32 to 47, described pharmaceutical composition includes enough water
To ensure 1mL cumulative volume.
50. the pharmaceutical composition according to any one of claim 32 to 49, described pharmaceutical composition is liquid suspension.
51. pharmaceutical composition according to claim 32, described pharmaceutical composition include:
(i) about 70mg/mL according to Shandong replaces Buddhist nun;
(ii) about 13mg/mL microcrystalline cellulose and sodium carboxymethylcellulose;
(iii) about 2.5mg/mL hydroxypropyl methyl cellulose;
(iv) about 1.5mg/mL citric acid monohydrate compound;
(v) about 1.4mg/mL disodium hydrogen phosphate;
(vi) about 1mg/mL Sucralose;
(vii) about 1mg/mL Sodium Methyl Hydroxybenzoate;With
(viii) about 0.6mg/mL nipagin A sodium.
52. pharmaceutical composition according to claim 32, described pharmaceutical composition include:
(i) about 40mg/mL according to Shandong replaces Buddhist nun;
(ii) about 14mg/mL microcrystalline cellulose and sodium carboxymethylcellulose;
(iii) about 1mg/mL hydroxypropyl methyl cellulose;
(iv) about 1.6mg/mL citric acid monohydrate compound;
(v) about 1.4mg/mL disodium hydrogen phosphate;
(vi) about 0.5mg/mL Sucralose;
(vii) about 1.4mg/mL Sodium Methyl Hydroxybenzoate;With
(viii) about 0.7mg/mL nipagin A sodium.
53. a kind of method for treating B cell proliferation disease, methods described includes according in claim 1 to 52 to appoint
Pharmaceutical composition described in one is administered to subject in need thereof.
54. method according to claim 53, wherein the B cell proliferation disease is NHL, Wa Er
Deng Sitelun macroglobulinemias, plasma cell myeloma or chronic lymphocytic leukemia.
55. method according to claim 54, wherein the NHL is selected from diffusivity large B cell lymph
Knurl, follicular lymphoma, lymphoma mantle cell and Burkitt lymphoma.
56. the method according to any one of claim 53 to 55, wherein the composition orally administers.
57. a kind of method for treating lymthoma, methods described is included according to any one of claim 1 to 52
Composition is administered to subject in need thereof.
58. a kind of method for treating leukaemia, methods described is included according to any one of claim 1 to 52
Composition is administered to subject in need thereof.
59. the set in a kind of at least one subject formerly treated received for treatment to lymphoma mantle cell is thin
The method of born of the same parents' lymthoma, methods described include once a day applying the composition according to any one of claim 1 to 52
With to the subject.
60. the method according to any one of claim 53 to 59, wherein the subject behaves.
61. the method according to any one of claim 53 to 60, wherein the composition is distributed in food.
62. method according to claim 61, wherein the food is pap.
63. method according to claim 61, wherein the subject is human child.
64. a kind of method for preparing composition according to claim 1, methods described includes:
(a) Ac-Di-Sol of microcrystalline cellulose, the NaLS of Part I and Part I is blended;
(b) product of step (a) and Part I are blended according to Shandong for Buddhist nun;
(c) product of step (b) and Part II are blended according to Shandong for Buddhist nun;
(d) magnesium stearate of the product of step (c) and Part I is blended;
(e) product of calandering steps (d);
(f) obtained ribbon in grinding steps (e);
(g) NaLS and Ac-Di-Sol of obtained particle in step (f) and Part II are blended;
And
(h) magnesium stearate of the product of step (g) and Part II is blended.
65. method according to claim 64, methods described also include:
(i) product of step (h) is added to capsule.
66. a kind of method for preparing composition according to claim 32, methods described includes:
(a) water, microcrystalline cellulose, Ac-Di-Sol are mixed;
(b) water and hydroxypropyl methyl cellulose are mixed;
(c) product of step (b) is mixed with according to Shandong for Buddhist nun;
(d) step (a) and (c) product are mixed;
(e) product of step (d) is mixed with Sucralose;
(f) product of step (e) is mixed with Sodium Methyl Hydroxybenzoate and nipagin A sodium;
(g) product of step (f) is mixed with monohydrate potassium;And
(h) product of step (g) is mixed with ADSP.
Priority Applications (1)
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CN202110822502.2A CN113546054A (en) | 2015-04-06 | 2016-04-06 | Composition comprising ibrutinib |
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US201562143659P | 2015-04-06 | 2015-04-06 | |
US62/143659 | 2015-04-06 | ||
PCT/US2016/026134 WO2016164404A1 (en) | 2015-04-06 | 2016-04-06 | Compositions containing ibrutinib |
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CN202110822502.2A Pending CN113546054A (en) | 2015-04-06 | 2016-04-06 | Composition comprising ibrutinib |
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CN113164782A (en) * | 2018-11-30 | 2021-07-23 | 詹森生物科技公司 | Method for treating follicular lymphoma |
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ES2971597T3 (en) | 2015-03-03 | 2024-06-06 | Pharmacyclics Llc | Bruton's Tyrosine Kinase Inhibitor Pharmaceutical Formulations |
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MX2020003760A (en) | 2017-09-26 | 2020-07-29 | Tesaro Inc | Niraparib formulations. |
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KR20190122561A (en) * | 2018-04-21 | 2019-10-30 | 류형준 | Lymphatic circulation promotor |
MA52874A (en) * | 2018-06-15 | 2021-04-21 | Janssen Pharmaceutica Nv | FORMULATIONS / COMPOSITIONS INCLUDING IBRUTINIB |
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KR102198502B1 (en) * | 2018-09-16 | 2021-01-05 | 류형준 | Food composition for lymphokinesis improvement in human organism |
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KR102251435B1 (en) * | 2020-11-09 | 2021-05-11 | 류형준 | Food composition for treating or alleviating edema by promotion of lymphokinesis |
US11433072B1 (en) * | 2021-06-10 | 2022-09-06 | Hikma Pharmaceuticals USA, Inc. | Oral dosage forms of ibrutinib |
WO2022260667A1 (en) * | 2021-06-10 | 2022-12-15 | Hikma Pharmaceuticals Usa Inc. | Oral dosage forms of ibrutinib |
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